Solid-phase electrophilic fluorination

ABSTRACT

The invention relates to compounds of formula (I); wherein R 1  and R 2  independently selected from C 1-6  alkyl; P 1 , P 2 , P 3 , and P 4  are each independently hydrogen or a protecting group; and their use in the preparation of  18 F-labelled 6-L-fluorodopa.

[0001] The present invention relates to novel solid-phase processes forthe production of radiolabelled tracers, in particular for theproduction of ¹⁸F-labelled 6-L-fluorodopa which may be suitable for useas a Positron·Emission Tomography (PET) tracer. The invention alsocomprises radiopharmaceutical kits using these novel processes.

[0002] The favoured isotope for PET, ¹⁸F, has a relatively shorthalf-life of 110 minutes. ¹⁸F-labelled tracers, such as6-L-¹⁸F-fluorodopa (6-¹⁸F-fluoro-3,4-dihydroxy-L-phenylalanine)(¹⁸F-FDOPA), for PET therefore have to be synthesised and purified asrapidly as possible and shortly before clinical use. Standard syntheticmethods for introducing fluorine-18 are relatively slow and requirepost-reaction purification (for example, by HPLC) which means that it isdifficult to obtain the ¹⁸F-labelled tracer for clinical use in goodradiochemical yield. ¹⁸F-FDOPA is widely used for monitoring cerebraldopamine metabolism.

[0003] The present invention provides solid-phase processes forproducing ¹⁸F-labelled tracers quickly yet avoiding time-consumingpurification steps, such that the resultant ¹⁸F-labelled tracer issuitable for use in PET. The solid-phase methods also lend themselves toautomation with advantages of ease of production and greater throughput.The invention also comprises radiopharmaceutical kits which use suchprocesses and thus provide the radiopharmacist or clinician with aconvenient means of preparing an ¹⁸F-labelled tracer.

[0004] Thus in a general aspect, the present invention provides aprocess for the production of 6-L-¹⁸F-fluorodopa (¹⁸F-FDOPA) whichcomprises treatment of a solid support-bound FDOPA precursor of formula(I):

[0005] wherein R¹ and R² independently selected from C₁₋₆ alkyl;

[0006] P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group;

[0007] with a source of ¹⁸F, suitably ¹⁸F₂, ¹⁸F-CH₃COOF or ¹⁸F-OF₂;

[0008] to give the labelled tracer of formula (II)

[0009] wherein P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group; optionally followed by:

[0010] (i) removal of excess fluorinating agent and ¹⁸F⁻ions produced inthe generation of the fluorinating agent or in the reaction; and/or

[0011] (ii) removal of any protecting groups; and/or

[0012] (iii) removal of organic solvent; and/or

[0013] (iv) formulation of the resultant compound of formula (II) as anaqueous solution.

[0014] In a preferred aspect, R¹ and R² are both methyl.

[0015] In the compounds of formula (I) and throughout this specificationunless otherwise stated, the “Solid Support” may be any suitablematerial which is insoluble in any solvents to be used in the processbut to which the “Linker” and/or FDOPA precursor can be covalentlybound. Examples of suitable solid support include polymers such aspolystyrene (which may be block grafted, for example, with polyethyleneglycol), polyacrylamide, and polypropylene or glass or silicon suitablycoated with such a polymer. The solid support may be in the form ofsmall discrete particles such as beads or pins, or as a coating on theinner surface of a cartridge or on a microfabricated vessel.

[0016] In the compounds of formula (I) and throughout thisspecification, the “Linker” may be any suitable organic group whichserves to space the reactive site sufficiently from the solid supportstructure so as to maximise reactivity. Suitably, the Linker comprisesan organic group of from 1 to 12 carbon atoms and from 0 to 6heteroatoms selected from oxygen, nitrogen, and sulphur. Examples ofsuch linkers are well known to those skilled in the art of solid-phasechemistry, but include:

[0017] wherein n is 0 to 10 and R is C₁₋₆ alkyl.

[0018] In a preferred aspect of the invention, the Linker is amethoxy-C₁₋₆alkyl group, most suitably, a methoxypropyl group.

[0019] As would be apparent to the person skilled in the art, it may benecessary to protect functional groups to avoid unwanted reactions inthe tracer. Such protection may be achieved using standard methods ofprotecting group chemistry. After the radiolabelling is complete, anyprotecting groups may be removed by simple procedures which are alsostandard in the art. Suitable protection and deprotection methodologiesmay be found, for example, in Protecting groups in organic synthesis,Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sonsinc, 605 third avenue, New York, N.Y. 10158-0012.

[0020] In each aspect of the invention, the acid functionality of theFDOPA precursor is conveniently protected as an ester, suitably C₁₋₆alkyl ester, the phenol functionalities of the FDOPA precursor areconveniently protected as carbonate ester, suitably C₁₋₆ alkyl carbonateesters and the amine functionality of the FDOPA precursor isconveniently protected as an amide, suitably a C₁₋₆ alkyl amide orurethane. In a preferred aspect, both P¹ and P² are t-butoxycarbonyl, P³is formyl or t-butoxycarbonyl, and P⁴ is ethyl. The protecting groupsmay be conveniently removed by hydrolysis (e.g. acid hydrolysis), forexample, at elevated temperature, such as 50° C. to 130° C., in thepresence of aqueous acid such as aqueous hydrobromic acid. Such acidhydrolysis may be followed by a neutralisation step, using an inorganicbase, for example, aqueous sodium hydroxide. Such deprotection may alsobe effected using solid supported acid catalysts that render the needfor post-deprotection neutralisation unnecessary. One example of such asolid supported acid catalyst would be a Dowex Sulphonate resin. Anaqueous solution of the optionally protected F-18 DOPA of formula (II)at elevated temperature, such as 50° C. to 130° C., would be treatedwith the resin to effect deprotection.

[0021] Treatment of the compound of formula (I) with ¹⁸F may be effectedby treatment with any suitable source of ¹⁸F, such as ¹⁸F₂, ¹⁸F-CH₃COOF,or ¹⁸F-OF₂, in the presence of a suitable organic solvent, suitably achlorofluorocarbon or fluorocarbon, such as trichlorofluoromethane, at anon-extreme temperature, for example, −10° C. to 60° C., preferably atambient temperature. On completion of the reaction, the ¹⁸F-labelledtracer of formula (II) dissolved in the solvent is convenientlyseparated from the solid-phase by filtration. The ¹⁸F₂ may be produced,for example, by the 20Ne(d,α) ¹⁸F reaction using the 13.5 Mev deuteronsof the Rossendorf cyclotron U-120 with Ne+0.2% F₂ (100 umol) as targetgas. Alternatively, the ¹⁸F₂ may be produced by the ¹⁸O₂ (p,n) ¹⁸Freaction, using 11 Mev protons from a cyclotron (A. J. Bishop et al, J.Nucl. Med., 32:1010(1991)).

[0022] Any excess fluorinating agent or ¹⁸F⁻ ions produced in thegeneration of the fluorinating agent or in the reaction and may beremoved from the solution of ¹⁸F-tracer of formula (II) by any suitablemeans, for example by passing through a column of sodium sulphite andsilica gel in a suitable solvent, suitably a chlorofluorocarbon or achlorocarbon, such as chlorofluoromethane or methylene chloride.

[0023] Any organic solvent may be removed by any standard method such asby evaporation at elevated temperature in vacuo or by passing a streamof an inert gas such as nitrogen, or argon over the solution.

[0024] Before use of the ¹⁸F-labelled DOPA, it may be appropriate toformulate it, for example as an aqueous solution by dissolving the¹⁸F-labelled tracer in sterile isotonic saline, which may contain up to10% of a suitable organic solvent such as ethanol, or a bufferedsolution such as phosphate buffer. Other additives may be added, forexample, a radio-stabiliser such as ascorbic acid, or a bacteriostatsuch as 4-hydroxybenzoic acid C₁₋₄ alkyl esters.

[0025] In a more specific aspect, the present invention provides aprocess for the production of 6-L-¹⁸F-fluorodopa (¹⁸F-FDOPA) whichcomprises treatment of a solid support-bound FDOPA precursor of formula(Ia):

[0026] wherein R¹ and R² independently selected from C₁₋₆ alkyl and arepreferably both methyl;

[0027] P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group;

[0028] with a source of ¹⁸F, suitably ¹⁸F₂, ¹⁸F-CH₃COOF, or ¹⁸F-OF₂;

[0029] to give the labelled tracer of formula (II):

[0030] wherein P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group; optionally followed by

[0031] (i) removal of excess fluorinating agent and ¹⁸F⁻ ions producedin the generation of the fluorinating agent or in the reaction; and/or

[0032] (ii) removal of any protecting groups such that P¹, P², P³, andP⁴ are each hydrogen; and/or

[0033] (iii) removal of organic solvent; and/or

[0034] (iv) formulation of the resultant compound of formula (II) as anaqueous solution.

[0035] The solid support-bound precursor of formula (Ia) may be preparedfrom commercially available starting materials as outlined in Scheme 1or Scheme 2.

[0036] Compounds of formulae (I) and (Ia) are novel and thus constitutefurther aspects of the present invention.

[0037] According to a further aspect, there is provided a process forthe preparation of a compound of formula (I) which comprises reaction ofa compound of formula (III)

[0038] wherein either:

[0039] R¹, R², R³, R⁴, and R⁵ are each independently selected from C₁₋₆alkyl and are each preferably methyl; or

[0040] R¹, R², R³, and R⁵ are each independently selected from C₁₋₆alkyl and are each preferably methyl and R⁴ is

[0041] with a compound of formula (IV)

[0042] wherein P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group. This reaction is suitably carried out in the presenceof a catalyst, suitably a palladium catalyst, such as Pd(0)(PR′₃)₄wherein R′ is selected from phenyl, phenyl substituted with 1 to 4organic groups, C₁₋₆ alkyl, or C₁₋₆ alkoxymethyl, a preferred catalystis palladium (0) tetrakistriphenylphosphine, and in the presence of anorganic base such as a trialkylamine, for example triethylamine, in asuitable solvent such as dimethoxyethane, at elevated temperature,typically at reflux.

[0043] In a more particular aspect of the invention, there is provided aprocess for the preparation of a compound of formula (Ia) whichcomprises reaction of a compound of formula (IIIa)

[0044] wherein either:

[0045] R¹, R², R³, R⁴, and R⁵ are each independently selected from C₁₋₆alkyl and are preferably each methyl; or

[0046] R¹, R², R³, and R⁵ are each independently selected from C₁₋₆alkyl and are each preferably methyl and R⁴ is

[0047] with a compound of formula (IV) as defined above. This reactionis suitably carried out in the presence of a catalyst, suitably apalladium catalyst, such as Pd(0)(PR′₃)₄ wherein R′ is selected fromphenyl, phenyl substituted with 1 to 4 organic groups, C₁₋₆alkyl, orC₁₋₆alkoxymethyl, a preferred catalyst is palladium (0)tetrakistriphenylphosphine, and in the presence of an organic base suchas a trialkylamine, for example triethylamine, in a suitable solventsuch as dimethoxyethane, at elevated temperature, typically at reflux.

[0048] As would be appreciated by the person skilled in the art, thischemistry may be applied to preparation of a solid support-boundprecursor for tracers other than FDOPA. Accordingly, in a more generalaspect of the invention, there is provided a process for the preparationof a compound of formula (V)

[0049] wherein R¹ and R² independently selected from C₁₋₆ alkyl and arepreferably both methyl, and phenyl ring “A” is optionally substitutedwith 1 to 5 organic groups; which comprises:

[0050] reaction of a compound of formula (III)

[0051] wherein either:

[0052] R¹, R², R³, R⁴, and R⁵ are each independently selected from C₁₋₆alkyl and are preferably each methyl; or

[0053] R¹, R², R³, and R⁵ are each independently selected from C₁₋₆alkyl and are each preferably methyl and R⁴ is

[0054] with the corresponding compound of formula (VI)

[0055] wherein phenyl ring “A” is substituted as described in thecompound of formula (V). This reaction is suitably carried out in thepresence of a catalyst, suitably a palladium catalyst, such asPd(0)(PR′₃)₄ wherein R′ is selected from phenyl, phenyl substituted with1 to 4 organic groups, C₁₋₆alkyl, or C₁₋₆alkoxymethyl, a preferredcatalyst is palladium (0) tetrakistriphenylphosphine, and in thepresence of an organic base such as a trialkylamine, for exampletriethylamine, in a suitable solvent such as dimethoxyethane, atelevated temperature, typically at reflux.

[0056] In formula (V) and in formula (Va) below, the “organic groups”which optionally form substituents on phenyl ring “A” are suitablyindependently selected from (a) halo, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆carboxylic acid or ester, an amine or amide group; and (b) saturated orunsaturated straight or branched chain, or cyclic systems comprisingfrom 1 to 12 carbon atoms and 0 to 4 heteroatoms each of which may beoptionally substituted by the groups listed in (a).

[0057] In a preferred embodiment of this aspect of the invention, thereis provided a process for the preparation of a compound of formula (Va)

[0058] wherein R¹ and R² independently selected from C₁₋₆ alkyl and arepreferably both methyl and phenyl ring “A” is optionally substitutedwith 1 to 5 organic groups; which comprises:

[0059] reaction of a compound of formula (IIIa):

[0060] wherein either:

[0061] R¹, R², R³, R⁴, and R⁵ are each independently selected from C₁₋₆alkyl and are preferably each methyl; or

[0062] R¹, R², R³, and R⁵ are each independently selected from C₁₋₆alkyl and are each preferably methyl and R⁴ is

[0063] with a compound of formula (VI) as defined above. This reactionis suitably carried out in the presence of a catalyst, suitably apalladium catalyst, such as Pd(0)(PR′₃)₄ wherein R′ is selected fromphenyl, phenyl substituted with 1 to 4 organic groups, C₁₋₆alkyl, orC₁₋₆alkoxymethyl, a preferred catalyst is palladium (0)tetrakistriphenylphosphine, and in the presence of an organic base suchas a trialkylamine, for example triethylamine, in a suitable solventsuch as dimethoxyethane, at elevated temperature, typically at reflux.

[0064] In a particular example of the above aspects, the compound offormula (VI) is2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane:

[0065] As described above, the advantages of such solid-phase processesfor preparation of ¹⁸F-labelled tracers include the relative speed ofthe process, simplified purification methods and ease of automation—allof which mean that the processes are suitable for preparation of¹⁸F-labelled tracers for use in PET. Accordingly, the present inventionprovides the use of a process for the manufacture of a ¹⁸F-labelledtracer of formula (II) for use in PET.

[0066] Conveniently, the solid support bound DOPA of formula (I) couldbe provided as part of a kit to a radiopharmacy. The kit may contain acartridge which can be plugged into a suitably adapted automatedsynthesiser. The cartridge may contain, apart from the solidsupport-bound FDOPA precursor, a column to remove unwanted fluoride ion,and an appropriate vessel connected so as to allow the reaction mixtureto be evaporated and allow the product to be formulated as required. Thereagents and solvents and other consumables required for the synthesismay also be included together with a compact disc carrying the softwarewhich allows the synthesiser to be operated in a way so as to meet thecustomers requirements for radioactive concentration, volumes, time ofdelivery etc.

[0067] Conveniently, all components of the kit are disposable tominimise the possibilities of contamination between runs and will besterile and quality assured.

[0068] The invention further provides a radiopharmaceutical kit for thepreparation of ¹⁸F-FDOPA for use in PET, which comprises:

[0069] (i) a vessel containing a compound of formula (I) or (Ia); and

[0070] (ii) means for eluting the vessel with a source of ¹⁸F; andoptionally

[0071] (iii) a cartridge for removal of excess fluorinating agent and¹⁸F⁻ ions; and optionally

[0072] (iv) a cartridge for solid-phase deprotection of the resultantproduct of formula (II).

[0073] The invention further provides a cartridge for aradiopharmaceutical kit for the preparation of ¹⁸F-FDOPA for use in PETwhich comprises:

[0074] (i) a vessel containing a compound of formula (I) or (Ia); and

[0075] (ii) means for eluting the vessel with a source of ¹⁸F.

[0076] In a further aspect of the invention, there is provided a methodfor obtaining a diagnostic PET image which comprises the step of using aradiopharmaceutical kit or a cartridge for a radiopharmaceutical kit asdescribed above.

[0077] The invention will now be illustrated by way of the followingExamples. Throughout the Examples, abbreviations used are as follows:

[0078] AcCN: Acetonitrile

[0079] AIBN: 2,2,-azobis(2-methylpropionitrile)

[0080] Boc: tert-Butoxycarbonyl

[0081] DCM: Dichloromethane

[0082] DMF: Dimethylormamide

[0083] Et: Ethyl

[0084] EtOH: Ethanol

[0085] h: hour(s)

[0086] HPLC: High-Performance-Liquid-Chromatography

[0087] I-DOPA:N-Formyl-3,4-di-t-butoxycarbonyloxy-6-Iodo-L-phenylalanine ethyl ester

[0088] MeOH: Methanol

[0089] min: minute(s)

[0090] NaH: Sodium hydride

[0091] N₂: Nitrogen

[0092] LiAlH₄: Lithiumaluminium hydride

[0093] Pd(PPh₃)₄: Tetrakistriphenylphosphine palladium

[0094] THF: Tetrahydrofuran

[0095] UV: Ultraviolet

Example 1 Preparation of Resin Bound Dimethyl Tin Protected Dopa Example1(i) Preparation of a Polymer Bound Allyl Ether From Merrifield Resin

[0096]

[0097] Starting material: Merrifield resin HL (100-200 mesh) Polystyrenecrosslinked with 2% Divinylbenzene (Novabiochem) Substitution: 1.6mMol/g. Method used was analogous to that described in Zhu et al (2000).Tetrahedron Lett., 41, 9219.

[0098] A solution of a 60% NaH dispersion in oil (Aldrich) (8 g, 0.2Mol) in dry DMF (60 mL) was cooled to 0° C. under N₂. To this solutionallyl alcohol (12.2 mL, 0.18 mMol) was added carefully over 30 min.under N₂. This solution was allowed to reach room temperature. After twohours stirring the alcoholate solution was transferred via cannula to aslurry containing Merrifield resin (10 g, 0.016 Mol) in dry DMF (40 mL)under N₂. The slurry was then very gently stirred with a small magneticstirrer for 20 h at 50° C. The reaction was quenched with EtOH to removethe excess of NaH. The resin is then washed with water, EtOH, MeOH,Acetone, DMF and DCM and dried in a vacuum oven at 40° C. for 16 hours.

Example 1 (ii) Hydrostannation of the Polymer Bound Allyl Ether

[0099]

[0100] The procedure first introduced by Neumann et al. (J. Pedain.(1962). Tetrahedron Lett., 3, 2461) that involves the use ofdimethylmonochlorotin hydride was used. This was obtained in situ byhalogen exchange between dimethyltindihydride and dimethyltindichloride(A. K. Sawyer, H. G. Kuivila. (1961). Chem. Ind., 260). For thepreparation of dimethyltindihydride the procedure published by Kuivilaet al. involving the use of tributyltinhydride as reducing agent wasused ((1971). J. Org. Chem., 36 (15), 2083).

[0101] Step 1. Preparation of Dimethyltindihydride

[0102] A 250 mL three necked flask equipped with a magnetic stirrer,addition funnel and an Argon balloon equipped with a tap was chargedwith dimethyltindichloride (14 g., 0.052 Mol). Glass tubing was used toconnect the flask consecutively to two receiving vessels cooled to −70°C. and to −180° C. respectively. Tributyltinhydride (66 mL, 0.24 Mol)was carefully added. Pressure in the system was reduced slowly to 20 mmHg with a water pump. The reaction vessel was heated to ca. 75° C. for30 min. until no more bubbling in the solution was observed.Approximately 7 mL of the product as a colorless liquid was obtained inthe first collection vessel at −70° C. This was used immediately for thefollowing reaction without further characterization. All processes werecarried out in an Argon atmosphere.

[0103] Step 2. Hydrostannation

[0104] Dimethyltindihydride (2.1 mL, 3.1 g, 0.02 Mol) was added with asyringe to a 250 mL two necked flask charged with a suspension ofpolymer (as prepared in Example 1(i)) (5 g, approx. 0.008 Mol),dimethyltindichloride (4.4 g., 0.02 Mol) and AIBN (100 mg, 0.6 mMol) indry benzene (60 mL). The suspension was irradiated with an UV Lamppositioned at about 25 cm. from the flask. A very gentle stirring with amagnet stirrer was applied. Another portion of a solution of AIBN (100mg, 0.6 mMol) in benzene (4 mL) was added to the suspension after 14 h.The temperature was maintained constant with a water bath in a Dewarvessel. All the processes were carried out in an Argon atmosphere. Totalreaction time was 48 h. The resin was then washed thoroughly withtoluene, methanol and acetone (approximately 100 mL each, with shakingof the suspension for 5 min., 3 cycles) and dried after a final wash ofether in a vacuum oven at 40° C. for 48 h. A grey resin (6.5 g) wasobtained.

[0105] Note: A long wave 100 W Ultraviolet Lamp (UVP: model B100AP,Fisher catalogue: LCF461-020V) was used.

Example 1 (iii) Reduction of Polymer Bound Tin Chloride to theCorresponding Tin Hydride

[0106]

[0107] A suspension of resin (as prepared in Example 1(ii)) (2 g,approx. 2.4 mMol) in freshly distilled THF (60 mL) in a 250 mLtwo-necked flask with a magnetic stirrer was cooled to 0° C. with an icebath. A solution 1M in THF of lithium aluminium hydride (Aldrich) (12mL, 12 mMol) was then slowly added to the suspension while a very gentlestirring was applied. A bubbling coming from the resin bead wasobserved. The reaction was allowed to warm to room temperature for 2 h.After that the resin was washed thoroughly with dry THF (100 mL, shakingfor approx. 5 min., 5 cycles) and dried with a stream of Argon. A graypolymer (1.8 g resin) was recovered.

Example 1 (iv) Solid-Phase Palladium Mediated Stannylation of I-Dopa

[0108]

[0109] The resin (as prepared in Example 1 (iii)) (500 mg, approximately0.6 mMol) was suspended in freshly distilled (CaH₂) and deoxygenated(Argon bubbling) 1-4 dioxane (15 mL) for 5 min. The catalyst (Pd(PPh₃))(208 mg; 0.18 mMol) was then added. The yellow mixture was stirredgently for 2 hours until no more H₂ evolution was observed.Di-O-t-butoxycarbonyl-6-iodo, N-formyl-Dopa ethyl ester (ABX, Radeberg,Germany) (1.2 g, 2 mMol) was then added. The mixture turned orangealmost immediately and a fine white precipitate was formed. The solventwas refluxed for 6 h. Thereafter the mixture was allowed to cool down,after which the resin was thoroughly washed with freshly distilleddioxane (30 ml, with shaking for about 5 min, 5 cycles). The resin wasthen dried first with a stream of Argon for 10 min. and later in avacuum oven at 40° C. for 16 h. A gray polymer (605 mg) was recovered.

COMPARATIVE EXAMPLE 2 Cleavage of I-DOPA From Resin Bound Dimethyl TinProtected Dopa Via Halodestannylation with Iodine

[0110] Aliquots of 20 mg of resin (prepared as described in Example1(iv)) (approx. 0.012 mMol) were suspended in dry dioxane (in 1 ml) in atest tube for 5 min. To the suspension iodine (25 mg, 0.1 mMol) wasadded and dissolved by gently shaking of the tube. After the reaction(30 min, 5 h. or 16 h) 1 mL of diethyl ether was added. The suspensionwas then washed with a solution 0.5N of sodium metabisulfite (1 ml). Theorganic layer (1 mL) was extracted with a pasteur pipette and evaporatedin vacuum. The extract was then dissolved in AcCN (1 ml) and analyzed byHPLC. Two aliquots of resin were exactly handled without addition ofiodine as a control.

[0111] Estimation of I-DOPA Release

[0112] The amount of I-DOPA released was determined by LC-UV-(MS).

[0113] Maximal theoretical substitution: 0.4 mMol/g (Assuming a 100%yield in all steps from the tin chloride resin), thus maximum yield from20 mg resin: (0.008 mMol) is approximately 5 mg. Concentration DOPAreleased Experiment Area mg/mL mg Yield % t = 30 min. 657 0.16 0.16 3.2t = 5 h 412 0.098 0.098 1.96 t = 16 h (1^(st) 31 7.4 * 10⁻³ 7.4 * 10⁻³0.15 extraction) t = 16 h (2nd 208 0.05 0.05 1 extraction) Control1 6.41.5 * 10⁻³ 1.5 * 10⁻³ 0.03 (30 min) Control2 (16 h) 12 2.8 * 10⁻³ 2.8 *10⁻³ 0.06 Blank — — — —

[0114] The results suggest that the addition of iodine promotes asignificant release of I-DOPA from the resin.

EXAMPLE 3 Cleavage [¹⁸F]-FDOPA from Resin Bound Dimethyl Tin ProtectedDopa Via Halodestannylation With [¹⁸F]-Fluorine

[0115] Radiolabelled [¹⁸F]F₂ is produced via ¹⁸O (p,n) ¹⁸F reaction andpassed directly from the cyclotron and bubbled through a suspension ofthe resin (prepared as described in Example 1 (iv) in Freon-11 at roomtemperature for a period of 2-3 minutes. The suspension is filtered andthe Freon-11 removed by evaporation. The residue is re-dissolved inmethanol and transferred to HPLC for analysis. A portion of the decayedmaterial is analysed by mass spectrometry and NMR.

1. A process for the production of 6-L-¹⁸F-fluorodopa (¹⁸F-FDOPA) whichcomprises treatment of a solid support-bound FDOPA precursor of formula(I):

wherein R¹ and R² independently selected from C₁₋₆ alkyl; P¹, P², P³,and P⁴ are each independently hydrogen or a protecting group; with asource of ¹⁸F, suitably ¹⁸F₂, ¹⁸F-CH₃COOF or ¹⁸F-OF₂; to give thelabelled tracer of formula (II)

wherein P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group; optionally followed by: (i) removal of excessfluorinating agent and ¹⁸F⁻ ions produced in the generation of thefluorinating agent or in the reaction; and/or (ii) removal of anyprotecting groups; and/or (iii) removal of organic solvent; and/or (iv)formulation of the resultant compound of formula (II) as an aqueoussolution.
 2. A process for the production of 6-L-¹⁸F-fluorodopa(¹⁸F-FDOPA) according to claim 1 which comprises treatment of a solidsupport-bound FDOPA precursor of formula (Ia):

wherein R¹ and R² independently selected from C₁₋₆ alkyl; P¹, P², P³,and P⁴ are each independently hydrogen or a protecting group; with asource of ¹⁸F, suitably ¹⁸F₂, ¹⁸F-CH₃COOF, or ¹⁸F-OF₂ to give thelabelled tracer of formula (II):

wherein P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group; optionally followed by (i) removal of excessfluorinating agent and ¹⁸F⁻ ions produced in the generation of thefluorinating agent or in the reaction; and/or (ii) removal of anyprotecting groups such that P¹, P², P³, and P⁴ are each hydrogen; and/or(iii) removal of organic solvent; and/or (iv) formulation of theresultant compound of formula (II) as an aqueous solution
 3. A compoundof formula (I):

as defined in claim
 1. 4. A compound of formula (Ia):

as defined in claim
 2. 5. A process for the preparation of a compound offormula (I) as defined in claim 1 which comprises reaction of a compoundof formula (III)

wherein either R¹, R², R³, R⁴, and R⁵ are each independently selectedfrom C₁₋₆ alkyl; or R¹, R², R³, and R⁵ are each independently selectedfrom C₁₋₆ alkyl and R⁴ is

with a compound of formula (IV)

wherein P¹, P², P³, and P⁴ are each independently hydrogen or aprotecting group.
 6. A process according to claim 5 for the preparationof a compound of formula (Ia) as defined in claim 2 which comprisesreaction of a compound of formula (IIIa)

wherein either R¹, R², R³, R⁴, and R⁵ are each independently selectedfrom C₁₋₆ alkyl; or R¹, R², R³, and R⁵ are each independently selectedfrom C₁₋₆ alkyl and R⁴ is

with a compound of formula (IV) as defined in claim
 5. 7. A process forthe preparation of a compound of formula (V)

wherein R¹ and R² independently selected from C₁₋₆ alkyl, and phenylring “A” is optionally substituted with 1 to 5 organic groups; whichcomprises: reaction of a compound of formula (III)

wherein either: R¹, R², R³, R⁴, and R⁵ are each independently selectedfrom C₁₋₆ alkyl; or R¹, R², R³, and R⁵ are each independently selectedfrom C₁₋₆ alkyl and R⁴ is

with the corresponding compound of formula (VI)

wherein phenyl ring “A” is substituted as described in the compound offormula (V).
 8. A process according to claim 7 for the preparation of acompound of formula (Va)

wherein R¹ and R² independently selected from C₁₋₆ alkyl and phenyl ring“A” is optionally substituted with 1 to 5 organic groups; whichcomprises: reaction of a compound of formula (IIIa):

wherein either R¹, R², R³, R⁴, and R⁵ are each independently selectedfrom C₁₋₆ alkyl; or R¹, R², R³, and R⁴ are each independently selectedfrom C₁₋₆ alkyl and R⁵ is

with a compound of formula (VI) as defined in claim
 7. 9. A processaccording to claim 7 or 8 wherein the compound of formula (VI) is2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane.10. A process for the manufacture of a ¹⁸F-labelled tracer of formula(II) as defined in claim 1 or 2 for use in PET.
 11. Aradiopharmaceutical kit for the preparation of ¹⁸F-FDOPA for use in PET,which comprises: (i) a vessel containing a compound of formula (I) or(Ia) as defined in claim 1 or 2 respectively; and (ii) means for elutingthe vessel with a source of ¹⁸F; and optionally (iii) a cartridge forremoval of excess fluorinating agent and ¹⁸F⁻ ions; and optionally (iv)a cartridge for solid-phase deprotection of the resultant product offormula (II) as defined in claim
 1. 12. A cartridge for aradiopharmaceutical kit for the preparation of ¹⁸F-FDOPA according toclaim 11 for use in PET which comprises: (i) a vessel containing acompound of formula (I) or (Ia) as defined in claim 1 or 2 respectively;and (ii) means for eluting the vessel with a source of ¹⁸F.
 13. A methodfor obtaining a diagnostic PET image which comprises the step of using aradiopharmaceutical kit according to claim 11 or a cartridge for aradiopharmaceutical kit according to claim 12.